published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

published_or_final_version / abstract / toc / Pharmacology / Master / Master of Philosophy

published_or_final_version / Pharmacology / Master / Master of Philosophy

Background: A beneficial effect of physical activity on the risk of cancer at several sites has been consistently observed. Biologic mechanisms that may underlie this relationship are not well understood. A potential mechanism explaining this relationship for some cancer sites is the influence of physical activity on methionine-homocysteine biosynthesis. High levels of total plasma homocysteine concentration (tHcy) indicate a breakdown in this biochemical process. This cycle’s influences on DNA methylation and endogeneous agents involved in oxidative stress are potential mechanisms linking methionine-homocysteine biosynthesis to cancer risk. This research is nested within a larger cross sectional study of healthy volunteers recruited from centers in Ontario and Nova Scotia aimed at understanding modifiable risk factors for cancer. Purpose: This research sought to elucidate the relationship between physical activity and tHcy level. Methods: The target population was healthy male and female subjects aged 20-50. Participants donate a 12ml blood sample after an overnight fast for analysis of tHcy and dietary factors and complete a questionnaire including a physical activity profile for the past month (adapted from the International Physical Activity Questionnaire [IPAQ]) and established predictors of tHcy level such as coffee and alcohol consumption. Multiple linear regression is used to model the relationship between tHcy and physical activity measures while controlling for potential confounders. Results: Analysis on 171 participants has been carried out. Mean tHcy for five quintiles of physical activity (from lowest physical activity score to highest) were found to be 8.40μmol/L (7.76-9.05), 8.60μmol/L (8.00, 9.22), 9.24μmol/L (8.66, 9.81), 8.23 μmol/L(7.64, 8.82), and 8.70μmol/L (8.09, 9.31). Conclusions: The findings of this research do not support a relationship between physical activity and total plasma homocysteine concentration. Results of this study suggest that homocysteine is not a mediating factor for the relationship observed between physical activity and cancer. / Thesis (Master, Community Health & Epidemiology) -- Queen's University, 2007-09-25 11:19:23.321

Background: Significant interest in homocysteine exists due to its established role in embryogenesis, cardiovascular disease and neurotoxicity. This research investigates total plasma homocysteine in the context of carcinogenesis among healthy individuals aged 20 to 50 years. It is hypothesized that during this timeframe, elevated total plasma homocysteine (tHcy) concentration implicates a breakdown of the methionine-homocyteine biosynthesis pathway, in which folate deficiency, oxidative stress and altered DNA methylation capacity are potential consequences relevant to cancer etiology. Purpose: The overall purpose of this research is to identify novel genetic predispositions to a biomarker of cancer risk (tHcy). Interactions with dietary and genetic factors that act on this pathway are explored. Methods: The study population consisted of 284 healthy male and female volunteers recruited in Kingston, Ontario and Halifax, Nova Scotia between 2006 and 2008. Specifically, polymorphisms under consideration included: i) the thymidylate synthase enhancer region (TSER) tandem repeat polymorphism and ii) the GC single nucleotide polymorphism (G/C SNP) both found on the 5’untranslated region (UTR) of the TS gene, and iii) the 6 base pair deletion at base pair 1494 (TS1494del6) found on the 3’UTR. TS polymorphisms were categorized based on either 5’ or 3’ location and were dichotomized to either high or low TS expression. Gene-gene interactions between polymorphisms in TS and methylenetetrahydrofolate reductase (MTHFR C677T) on tHcy concentration were also analyzed. In addition, gene-diet interactions between serum folate and vitamin B12 status were examined. Results: Mean tHcy concentration for this study population was 8.65 µmol/L (standard deviation=1.96 µmol/L). After adjustment for confounders, higher mean tHcy levels of 0.48 μmol/L and 0.46 μmol/L were observed for the main effects of 5’polymorphisms (5’High) (p=0.04) and 3’polymorphism (3’High) (p=0.05), respectively. The largest difference in mean tHcy concentration was observed for the joint effects of TS polymorphisms (µ=0.74 μmol/L, p=0.11). Gene-gene interaction was observed between TS and MTHFR polymorphisms on tHcy concentrations (p<0.01). Conclusions: The findings of this research provide evidence of an association between TS polymorphisms and tHcy concentrations. These results suggest that TS polymorphisms, independent of dietary factors, may lead to elevated tHcy levels and potentially contribute to cancer development. / Thesis (Master, Community Health & Epidemiology) -- Queen's University, 2008-08-21 16:05:02.797

BACKGROUND: Evidence supports that an elevated level of total plasma homocysteine (tHcy) signifies a breakdown in the methionine-homocysteine cycle. This may result in folate deficiency, DNA methylation and oxidative stress, all of which are potential mechanisms that may lead to cancer. Few studies examined the effects of alcohol consumption on tHcy levels. No studies considered polymorphisms in alcohol dehydrogenase 1C (ADH1C), a gene that encodes for an enzyme that metabolizes alcohol to acetaldehyde, a folate antagonist; ADH1C*1 encodes for an enzyme with a higher capacity to generate acetaldehyde than ADH1C*2. PURPOSE: This study examined the association between alcohol intake and risk of elevated tHcy while exploring a potential gene-environment interaction with polymorphisms in ADH1C. METHOD: This was a case-control study nested in a larger cross-sectional study funded by Canadian Institutes of Health Research. The target population was recruited from Kingston and Halifax from 2006 to 2008 and included 100 cases and 187 controls selected from healthy male and female subjects aged 20-50 years. Cases were defined as subjects with tHcy ≥ 10 mol/L and controls < 10 mol/L. Alcohol consumption was categorized into three groups: ≤12.0 g/day, 12.1–24.0 g/day, and >24.0 g/day. ADH1C was dichotomized by collapsing ADH1C*1/*2 and ADH1C*2/*2 into one group and examined against ADH1C*1/*1. RESULTS: Compared to ≤12.0 g/day, odds ratio (OR) for 12.1-24.0 g/day was 0.53 [95% confidence interval (CI), 0.25-1.13] and for >24.0 g/day was 1.19 (95% CI, 0.60-2.24), suggesting a J-shaped trend with risk of elevated tHcy. A reduced OR was observed for ADH1C*1/*1 (OR= 0.52, 95% CI, 0.27-1.03). The alcohol-ADH1C interaction was not statistically significant (p-value = 0.21), though a stronger J-shape trend was suggested in ADH1C*1/*1. Among consumers of ≤12.0 g/day, a reduced measure of effect was observed for ADH1C*1/*1 (OR= 0.44, 95% CI, 0.19-1.00). CONCLUSION: A J-shaped trend was suspected between risk of elevated tHcy and alcohol consumption. Additionally, a nonsignificant reduced effect of ADH1C*1/*1 on risk of elevated tHcy, with a more pronounced effect in the lowest group of alcohol consumption. This suggests that ADH1C may be associated to homocysteine through factors unrelated to alcohol intake. / Thesis (Master, Community Health & Epidemiology) -- Queen's University, 2008-09-26 21:06:15.185

Hyperhomocysteinemia, a condition of elevated blood homocysteine (Hcy) level, is an independent risk factor for cardiovascular disease. Folic acid supplementation can effectively reduce blood Hcy levels. Recent studies have demonstrated that hyperhomocysteinemia is also associated with kidney disease. However, the underlying mechanisms remain unclear. The overall objective of the study was to investigate the biochemical and molecular mechanisms of Hcy-induced kidney injury and the effect of folic acid supplementation on Hcy-induced kidney injury. Hyperhomocysteinemia was induced in Sprague-Dawley rats by feeding a high-methionine diet for 12 weeks. An elevation of serum total Hcy level was observed in hyperhomocysteinemic rats. Hyperhomocysteinemia-induced superoxide anion production via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation resulted in oxidative stress in the kidney. Reduction of oxidative stress by inhibiting superoxide anion production effectively ameliorated hyperhomocysteinemia-induced kidney injury. Inflammatory responses such as increased chemokine expression have been implicated as one of the mechanisms of kidney disease. Monocyte chemoattractant protein-1 (MCP-1) is a potent chemokine that is involved in the inflammatory response in kidney disease. Nuclear factor-kappa B (NF-kappaB) plays an important role in upregulation of MCP-1 expression. We investigated the effect of hyperhomocysteinemia on MCP-1 expression and the molecular mechanism responsible for such an effect in rat kidneys as well as in human kidney proximal tubular cells.

Hyperhomocysteinemia, a condition of elevated blood homocysteine (Hcy) level, is an independent risk factor for cardiovascular disease. Folic acid supplementation can effectively reduce blood Hcy levels. Recent studies have demonstrated that hyperhomocysteinemia is also associated with kidney disease. However, the underlying mechanisms remain unclear. The overall objective of the study was to investigate the biochemical and molecular mechanisms of Hcy-induced kidney injury and the effect of folic acid supplementation on Hcy-induced kidney injury. Hyperhomocysteinemia was induced in Sprague-Dawley rats by feeding a high-methionine diet for 12 weeks. An elevation of serum total Hcy level was observed in hyperhomocysteinemic rats. Hyperhomocysteinemia-induced superoxide anion production via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation resulted in oxidative stress in the kidney. Reduction of oxidative stress by inhibiting superoxide anion production effectively ameliorated hyperhomocysteinemia-induced kidney injury. Inflammatory responses such as increased chemokine expression have been implicated as one of the mechanisms of kidney disease. Monocyte chemoattractant protein-1 (MCP-1) is a potent chemokine that is involved in the inflammatory response in kidney disease. Nuclear factor-kappa B (NF-kappaB) plays an important role in upregulation of MCP-1 expression. We investigated the effect of hyperhomocysteinemia on MCP-1 expression and the molecular mechanism responsible for such an effect in rat kidneys as well as in human kidney proximal tubular cells.

Elevated serum homocysteine concentrations are neurotoxic and are strongly implicated as a risk factor for neuropsychiatric disease (Fabender, Mielke, Bertsch, & Hennerici, 1999; Kim & Pae, 1996; Kruman et al., 2000; Reutens & Sachdev, 2002). This study compares homocysteine levels in early stages psychosis patients and healthy controls. Data from 48 healthy controls were compared with 50 previously diagnosed psychosis patients, 15-25 years, and with a gender ratio males: females 7:3. Patients were outpatients or inpatients at ORYGEN Youth Health, with a diagnosis of first episode of psychosis defined as daily psychotic symptoms lasting longer than a week that could not be explained by other means such as “drug-induced” or “organic”. / All subjects were interviewed to collect information relating to family psychotic history. A possible history of psychotic disease in control subjects was tested using the SCID Psych Screening Module, drug use recorded using Alcohol Use Disorders Identification Test (AUDIT) (for alcohol use), The Modified Fagerström Tolerance Questionnaire (mFTQ) (for smoking), Opiate Treatment Index (OTI) (for opiate-type drugs). Dietary and medication histories were also taken. Blood tests were performed to determine serum homocysteine, serum folate, red blood cell folate and serum vitamin B12 levels. / An independent sample t test to compare homocysteine levels in patients and controls was performed. Serum homocysteine levels were significantly higher for patients (M = 12.9, S.D. = 3.6) than controls (M = 11.1, S.D. = 2.7) (t(96) = 2.7, p = 0.007, two-tailed). After General Linear Model (GLM) analysis it was found that group (patients or controls), and not serum folate, vitamin B12 and the T allele of MTHFR C677 polymorphism had significant effect on homocysteine levels. Thus a number of factors that may increase homocysteine levels were ruled out. / Although it was not possible to obtain a complete data set for some factors (alcohol, smoking and caffeine consumption) (a weakness of the study), strengths included consecutive recruitment, minimisation of selection bias, good matching for age and gender between patients and controls, and the consideration of (serum) folate and (serum) vitamin B12 as potential confounding variables. / A number of other studies have found significantly increased homocysteine levels in young patients compared with controls, particularly males. Most related studies favoured the homocysteine-psychosis link. / The probability of symptomatic recovery is very high (80-90%) after treatment for first episode psychosis (Robinson et al., 1999) and delayed treatment, but prolonged duration of treatment is associated with poorer response in treatment and worse outcome (Malla & Norman, 2002). This justifies studying homocysteine levels and cognitive function in that first period of psychosis. / This research offers evidence for the importance of serum homocysteine levels as showing involvement in the etiology of psychosis. Lowering homocysteine may have a beneficial effect on symptoms and cognitive dysfunction in psychotic illness. / Two randomised controlled trials have demonstrated benefit in psychotic illness of giving folate and consequently reducing homocysteine.(Godfrey & Toone, 1990; Levine et al., 2006b). Benefits of taking folate were found in both trials for both cognition and psychotic symptoms. By reducing homocysteine levels early in the illness, some of the excess cardiovascular mortality may be prevented. / Secondary prevention of CVD does not appear to influence outcome (Hermann, Herrmann, & Obeid, 2007), so the right time to intervene and reduce risk would appear to be early in the course of psychosis. Additionally, by lowering homocysteine cognitive functioning and psychotic symptoms may be improved (Levine et al., 2006b).

Thesis (M. Med. Sc.)--University of Hong Kong, 2000. / Includes bibliographical references (leaves 57-60).